This article reads: "In my own clinical experience, most cases of refractory bipolardisorder, usually of the rapid-cycling variety, are due to themood-destabilizing effects of antidepressants."

Last paragraph reads: "In sum, like other results from STEP-BD, this study may be onemore nail in the coffin of antidepressant use in bipolar disorder.It would seem rational to turn our attention from antidepressantstoward better proven interventions, particularly psychotherapies(10), for the depressive morbidity of bipolar disorder."

A century ago, rapid-cycling bipolar disorder was not observed.Either classic nosologists, such as Kraepelin, simply missedit or it did not exist. The term was first coined in the 1970sto identify lithium nonresponders in randomized clinical trials;thereafter, rapid cycling became the subject of decades of furtherresearch, which has confirmed that rapid cycling is a factorin poor prognosis. Rapid-cycling patients do worse in follow-upthan patients without rapid cycling, and they are also lesslikely to respond to treatment. The erroneous impression thenarose that anticonvulsants, such as carbamazepine or divalproex,were more effective than lithium in treating rapid cycling.The error came from comparing studies using lithium alone againststudies using anticonvulsants alone, without a direct comparisonof the two treatments. Such comparisons need to be made headto head, in randomized studies. When these comparisons are performedwith proper methods, anticonvulsants are seen to be about equivalentto lithium (i.e., ineffective) in treating rapid cycling (1,2).

Because rapid cycling was not described until the 1970s, cliniciansbegan speculating that psychotropics, such as antidepressants,induce rapid cycling. Is rapid cycling iatrogenic? Do antidepressantsperhaps increase the risk for rapid cycling or worsen symptomsin some patients? Early reports of a possible link between antidepressantsand rapid cycling were made in the 1970s by Kukopulos in Italy(3) and by Wehr et al. at NIMH (4). Later observational studieswere contradictory and inconclusive (5). Yet the largest publishedrandomized clinical trial showed that discontinuation of antidepressantmedication improved refractory rapid cycling (4). This studyfound an association between tricyclic antidepressant treatmentand rapid cycling in a double-blind, placebo-controlled on-off-on-offdesign, although the published report was incomplete in manydetails. Nonetheless, the implication, that antidepressantscause rapid cycling, was intriguing; this finding potentiallygives clinicians an important tool to improve outcome in bipolardisorder: discontinuation of antidepressants. Yet this approachgoes against some of the tendencies of physicians: giving, notstopping, medications to improve mental illnesses.

In this issue of the Journal, Schneck and colleagues reportnew data from the NIMH-sponsored Systematic Treatment EnhancementProgram for Bipolar Disorder (STEP-BD) study, in which aboutone-third of the patients with bipolar disorder had rapid cycling;these patients also had more recurrences in the 1-year followup. Only 5% of these rapid-cycling patients continued to meetthat definition (four or more episodes in a year) at the 1-yearfollow up, either because of appropriate treatment in STEP-BDor because of natural history. The major predictor of worseoutcome was antidepressant use, which about 60% of the patientsreceived, most often accompanied by mood stabilizers.

By focusing on the relationship between antidepressant use andrapid cycling, the STEP-BD study fills an important void. Notonly is the study far larger (N=1,742) than any prior investigation,it is also prospective, unlike all but one prior observationalstudy (6). Moreover, unlike that study, this STEP-BD study showsthat antidepressants are associated with worsened course ofillness even after adjustment for severity of baseline depression.

The aforementioned largest randomized clinical trial of rapidcycling (N=51), although not definitive, also indicated an associationbetween antidepressant use and rapid cycling (4). In contrast,a recent small study (N=9) of previously untreated patientswith type II rapid-cycling bipolar disorder showed benefit withcitalopram (7), but that study was limited to type II bipolarillness. Further, those data do not apply to patients with refractoryillness. Now the largest prospective observational study hasconfirmed the association of rapid cycling with antidepressantuse, supporting the viewpoint that these agents can worsen overallillness, causing more mood episodes (including depression),in patients with a rapid-cycling course.

Critics may suggest that the available randomized clinical trialsof maintenance treatment for bipolar disorder do not uniformlyprovide evidence of increased cycling rates with antidepressants.As has been discussed at length elsewhere (5), it is relevantthat those trials were conducted with mostly non-rapid-cyclingpatients and were not powered to detect long-term worseningof mood episodes with antidepressants, compared with placebo.In the future, it will be difficult, as well as ethically challenging,to devise randomized clinical trials to test the hypothesisof worsening of rapid-cycling bipolar disorder with antidepressants.Thus, observational analyses such as this STEP-BD study willbecome even more influential for informing clinical care.

In my own clinical experience, most cases of refractory bipolardisorder, usually of the rapid-cycling variety, are due to themood-destabilizing effects of antidepressants. Such patientsoften receive antidepressants for years, with or without moodstabilizers. They rarely receive mood stabilizers in the absenceof antidepressants. If antidepressants are seen as mood destabilizers,then an adequate therapeutic trial of mood stabilizers for rapidcycling can occur only in the absence of antidepressants. Frequently,in patients with refractory rapid-cycling bipolar disorder,multiple trials of mood stabilizers appear to fail, as the dataof Schneck et al. suggest, because they are evaluated with antidepressants.When antidepressants are stopped, those same mood-stabilizingagents can then be effective. Stopping antidepressants thusis the sine qua non of treating rapid-cycling bipolar disorder.Sometimes, in a minority of cases, usually with highly suicidalpatients during depressive episodes, short-term antidepressanttreatment may be warranted. But in most patients with rapidcycling, these mood destabilizers are best avoided.

Mood destabilization with antidepressants should be distinguishedfrom an acute manic "switch." Antidepressant-induced mania,or switch, is a short-term phenomenon; one might define it ashappening within 2 months of the beginning of antidepressanttreatment. Mood destabilization is a long-term phenomenon, reflectingmore mood episodes over time than would have occurred by naturalhistory. Antidepressants may cause long-term mood destabilizationwithout a short-term manic switch, and vice versa. Althoughsome agents may have low rates of acute manic switch (8), especiallywhen used with mood stabilizers (9), the data from STEP-BD suggestthat even the new generation of antidepressants can producelong-term mood destabilization.

In sum, like other results from STEP-BD, this study may be onemore nail in the coffin of antidepressant use in bipolar disorder.It would seem rational to turn our attention from antidepressantstoward better proven interventions, particularly psychotherapies(10), for the depressive morbidity of bipolar disorder.

Dr. Ghaemi reports research funding from GlaxoSmithKline andPfizer; serves on the speakers bureaus of GlaxoSmithKline, AstraZeneca,Pfizer, Janssen, and Abbott Laboratories; and has served onthe advisory boards of GlaxoSmithKline, Janssen, Pfizer, Shire,and Abbott Laboratories. Dr. Freedman has reviewed this editorialand found no evidence of influence from these relationships.